The epilepsies are a diverse group of disorders characterized by abnormal electrical activity in the CNS, affecting up to 3% of the population. Of this group, approximately 40% are idiopathic in which the underlying cause is most likely a genetic abnormality. The specific abnormality has been identified in only a small minority of cases, most of which are channelopathies involving defects in ion channel function. Even in those cases, the mechanisms by which the defects result in epilepsy are not understood. One class of channelopathies that cause epilepsy are mutations in voltage-gated sodium channels, which cause a number of different syndromes including Generalized Epilepsy with Febrile Seizures Plus (GEFS+). The goal of this research is to determine how abnormal sodium channel function resulting from mutations causing GEFS+ leads to epilepsy. There are four goals. The first aim is to determine if different mutations cause GEFS+ by altering sodium channel function in different ways. This will be accomplished by determining the electrophysiological properties of GEFS+ mutants after expression in Xenopus oocytes and transfected mammalian cells. The second aim is to determine if the mutations that cause GEFS+ alter neuronal excitability. This will be accomplished by expressing the mutant channels in primary cortical neurons followed by characterization of neuronal firing using current-clamping. The third aim is to determine if the mutations that cause GEFS+ in humans can cause epilepsy in mice. This will be accomplished by constructing both transgenic and knock-in mice expressing different sodium channel mutations. The mice will provide a model system for studying neuronal excitability in native cells and for studying the development of seizures. The final aim is to determine if comparable mutations in other sodium channel genes can cause epilepsy. Although there are three sodium channel isoforms in the adult mammalian CNS, all of the mutations that are known to cause GEFS+ are in two of the genes, those encoding Na[v]1.1 and Na[v]1.2. We will construct comparable mutations in the other adult CNS isoform (Na[v]1.6) and determine if the mutations alter the properties of those channels in a similar manner. We will also construct transgenic mice expressing those mutant channels to determine if they cause epilepsy or other neurological disorders. These studies should enhance our knowledge concerning the physiological events leading to epilepsy and will provide a model system that can be used to study the development of epilepsy in a controlled manner.